title: Irradiation leads to sensitization of hepatocytes to TNF-alpha-mediated apoptosis by upregulation of IkappaB expression.
abstract: This study aimed to reveal the pathophysiological signalling responsible for radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis. IkappaB was upregulated in irradiated hepatocytes. Administration of IkappaB antisense oligonucleotides prior to irradiation inhibited occurrence of apoptosis after TNF-alpha administration. Caspases-8, -9 and -3 activities were increased in irradiated hepatocytes and downregulation of apoptosis by IkappaB antisense oligonucleotides was mediated by suppression of caspases-9 and -3 activation but not of caspase-8 activation, suggesting that radiation-induced sensitization of hepatocytes to TNF-alpha-mediated apoptosis additionally requires changes upstream of caspase-8 activation. Herein, upregulation of FLIP may play a crucial role. Cleavage of bid, upregulation of bax, downregulation of bcl-2 and release of cytochrome c after TNF-alpha-administration depend on radiation-induced upregulation of IkappaB, thus demonstrating an apoptosis permitting effect of IkappaB.
authors.affiliation: Section of Gastroenterology and Endocrinology, Department of Internal Medicine, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gürleyen
authors.forename: Hans
authors.initials: H
authors.lastname: Christiansen
authors.forename: Khodr
authors.initials: K
authors.lastname: Tello
authors.forename: Joszef
authors.initials: J
authors.lastname: Dudas
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hermann
authors.forename: Margret
authors.initials: M
authors.lastname: Rave-Fränk
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Hess
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ramadori
authors.forename: Bernhard
authors.initials: B
authors.lastname: Saile
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D011829:Radiation Dosage; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000528:radiation effects*
chemical_list: D051017:Apoptosis Regulatory Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c